Despite recent advances in multimodality therapy for glioblastoma (GB) incorporating surgery, radiotherapy, chemotherapy and targeted therapy, the overall prognosis remains poor. One of the interesting targets for GB therapy is the histone deacetylase family (HDAC). Due to their pleiotropic effects on, e.g., DNA repair, cell proliferation, differentiation, apoptosis and cell cycle, HDAC inhibitors have gained a lot of attention in the last decade as anti-cancer agents. Despite their known underlying mechanism, their therapeutic activity is not well-defined. In this review, an extensive overview is given of the current status of HDAC inhibitors for GB therapy, followed by an overview of current HDAC-targeting radiopharmaceuticals. Imaging HDAC expression or activity could provide key insights regarding the role of HDAC enzymes in gliomagenesis, thus identifying patients likely to benefit from HDACi-targeted therapy.
Personalised dosimetry based on molecular imaging is a field that has grown exponentially in the last decade due to the increasing success of Radioligand Therapy (RLT). Despite advances in imaging-based 3D dose estimation, the administered dose of a therapeutic radiopharmaceutical for RLT is often non-personalised, with standardised dose regimens administered every 4–6 weeks. Biodosimetry markers, such as chromosomal aberrations, could be used alongside image-based dosimetry as a tool for individualised dose estimation to further understand normal tissue toxicity and refine the administered dose. In this review we give an overview of biodosimetry markers that are used for blood dose estimation, followed by an overview of their current results when applied in RLT patients. Finally, an in-depth discussion will provide a perspective on the potential for the use of biodosimetry in the nuclear medicine clinic.
Following population declines of the African savanna elephant (Loxodonta africana) across the African continent, the establishment of primary cell lines of endangered wildlife species is paramount for the preservation of their genetic resources. In addition, it allows molecular and functional studies on the cancer suppression mechanisms of elephants, which have previously been linked to a redundancy of tumor suppressor gene TP53. This methodology describes the establishment of primary elephant dermal fibroblast (EDF) cell lines from skin punch biopsy samples (diameter: ±4 mm) of African savanna elephants (n = 4, 14-35 years). The applied tissue collection technique is minimally invasive and paves the way for future remote biopsy darting. On average, the first explant outgrowth was observed after 15.75 ± 6.30 days. The average doubling time (Td) was 93.02 ± 16.94 h and 52.39 ± 0.46 h at passage 1 and 4, respectively. Metaphase spreads confirmed the diploid number of 56 chromosomes. The successful establishment of EDF cell lines allows for future elephant cell characterization studies and for research on the cancer resistance mechanisms of elephants, which can be harnessed for human cancer prevention and treatment and contributes to the conservation of their genetic material.
Abstract The radiosensitivity of haematopoietic stem and progenitor cells (HSPCs) to neutron radiation remains largely underexplored, notwithstanding their potential role as target cells for radiation-induced leukemogenesis. New insights are required for radiation protection purposes, particularly for aviation, space missions, nuclear accidents and even particle therapy. In this study, HSPCs (CD34 + CD38 + cells) were isolated from umbilical cord blood and irradiated with 60 Co γ-rays (photons) and high energy p(66)/Be(40) neutrons. At 2 h post-irradiation, a significantly higher number of 1.28 ± 0.12 γ-H2AX foci/cell was observed after 0.5 Gy neutrons compared to 0.84 ± 0.14 foci/cell for photons, but this decreased to similar levels for both radiation qualities after 18 h. However, a significant difference in late apoptosis was observed with Annexin-V + /PI + assay between photon and neutron irradiation at 18 h, 43.17 ± 6.10% versus 55.55 ± 4.87%, respectively. A significant increase in MN frequency was observed after both 0.5 and 1 Gy neutron irradiation compared to photons illustrating higher levels of neutron-induced cytogenetic damage, while there was no difference in the nuclear division index between both radiation qualities. The results point towards a higher induction of DNA damage after neutron irradiation in HSPCs followed by error-prone DNA repair, which contributes to genomic instability and a higher risk of leukemogenesis.
1379 Objectives Discrimination between HGG and RN remains a diagnostic challenge because both entities have similar imaging characteristics on conventional MRI. Metabolic imaging, such as PET could aid in this diagnostic dilemma. In this study, we investigated the potential of F18-FDG, F18-FCho and F18-FET PET in discriminating HGG from RN. Methods On day 15 after inoculation of F98 glioblastoma (GB) cells in the rat brain, MRI showed a contrast-enhancing tumor. μPET was performed (dynamic F18-FDG PET at conventional intervals followed by a delayed (240 min p.i.) acquisition, dynamic F18-FCho and F18-FET PET, n=4). Induction of RN was achieved by irradiating the right frontal region with 60 Gy using 3 arcs of 3*3mm. Follow-up MRI scans revealed a contrast-enhancing RN lesion 6-7 months post-irradiation and μPET was performed (n=3). The time activity curves (TACs) of the mean standard uptake value (SUV) and the lesion-to-normal tissue uptake ratio (LNR) measured during the last time frame were compared between GB and RN (see figure). Results On conventional F18-FDG PET, mean LNR in GB (1.35±0.08) was higher compared to RN (1.04±0.08) and were significantly different (p=0.034). The difference in LNR was higher on the delayed F18-FDG scan (1.60±0.25 in GB and 1.06±0.01 in RN), however borderline significant (p=0.064) due to the small sample size (n=2). For F18-FCho, LNRs in GB and RN were 2.55±0.39 and 2.45±0.16, respectively and not significanlty different (p=1.000), meaning that 18F-FCho cannot discriminate between GB and RN. F18-FET uptake was higher in GB with a LNR of 2.19±0.16, while a LNR of 1.71±0.32 was shown in RN. F18-FET LNRs were significantly higher in GB than in RN (p=0.034). Conclusions Based on these results, F18-FDG and F18-FET PET were able to discriminate GB from RN whereas F18-FCho was not. However, because there was visible uptake of F18-FET in RN (not shown) , a threshold will be necessary.
Purpose: Discrimination between glioblastoma (GB) and radiation necrosis (RN) remains challenging using conventional MRI. However, a correct diagnosis is important for patient management. We hypothesised that based on differences in vascular properties, such as vascular density, vascular permeability, blood flow, composition of the extracellular and extravascular space and interstitial pressure, dynamic contrast-enhanced (DCE) MRI would allow to distinguish GB from RN. As such, in this study, the potential of semi-quantitative and quantitative analysis of DCE-MRI was investigated to differentiate GB from RN in rats. Procedures: F98 GB cells were inoculated in the rat brain. GB growth was seen on follow-up MRI 8–23 days post-inoculation (n=15). RN lesions developed 6–8 months post-irradiation (n=10). DCE-MRI was acquired using a fast low angle shot (FLASH) sequence. Regions of interest (ROIs) encompassed peripheral contrast-enhancement in GB (n=15) and RN (n=10) as well as central necrosis within these lesions (GB (n=4), RN (n=3)). DCE-MRI data were fitted to determine 4 function variables (amplitude A, offset from zero C, wash-in rate k and wash-out rate D) as well as maximal intensity (ImaxF) and time-to-peak (TTPF). Secondly, maps of semi-quantitative and quantitative parameters (extended Tofts model) were created using Olea sphere (O). Semi-quantitative DCE-MRI parameters included wash-inO, wash-outO, area under the curve (AUCO), maximal intensity (ImaxO) and time-to-peak (TTPO). Quantitative parameters included the rate constant plasma to extravascular-extracellular space (EES) (Ktrans), the rate constant EES to plasma (Kep), plasma volume (Vp) and EES volume (Ve). All (semi-)quantitative parameters were compared between GB and RN using the Mann-Whitney U test and ROC analysis was performed. Results: Wash-in rates (k and wash-inO) were significantly higher in GB compared to RN (p=0.016 and p=0.041, respectively). Wash-out rate (D) was only significantly higher in GB using curve fitting (p=0.014). TTPF and TTPO were significantly lower in GB compared to RN (p=0.001 and p < 0.001, respectively). The highest sensitivity (93%) and specificity (90%) was obtained for TTPO by applying a threshold of 415 s. Ktrans, Kep, Vp and Ve were not significantly different between GB and RN. Conclusions: Based on our results in a rat model, DCE-MRI may be useful to discriminate GB from RN. Wash-in rates (k and wash-inO), TTPF and TTPO, which can be derived from a 5-min DCE-MRI acquisition, are able to distinguish GB from RN while other quantitative and semi-quantitative parameters are not. Whether DCE-MRI will also be able to differentiate GB from RN in humans must be further explored.
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